A new synthesis of angelicin from 7-hydroxycoumarin via c-propenation-o-vinylation and ring-closing metathesis

Article abstract of DOI:10.1002/jccs.200400152

A new and concise method for the synthesis of angelicin was described. 7-Hydroxycoumarin was converted into angelicin in good overall yields via the process of c-propenation-o-vinylation and ring-closing metathesis (RCM).

Full text of DOI:10.1002/jccs.200400152

Journal of the Chinese Chemical Society, 2004, 51, 1019-1023
1019
A New Synthesis of Angelicin from 7-Hydroxycoumarin via
C-Propenation-O-Vinylation and Ring-Closing Metathesis
Tzu-Wei Tsaia,b
(
) and Eng-Chi Wanga* (
)
aFaculty of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan, R.O.C.
bGraduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan, R.O.C.
A new and concise method for the synthesis of angelicin was described. 7-Hydroxycoumarin was con-
verted into angelicin in good overall yields via the process of c-propenation-o-vinylation and ring-closing me-
tathesis (RCM).
Keywords: Claisen rearrangement; RCM; Angelicin.
INTRODUCTION
Angelicin, 2H-furo[2,3-h]chromene-2-one, a naturally
this our continuing studies, herein we would like to disclose a
new method for the preparation of angelicin by the following
protocols (Scheme I): (i) 7-allyloxycoumarin (2), prepared
from 7-hydroxycoumarin (1), was subjected to the Claisen re-
arrangement to furnish c-allylation to give 8-allyl-7-hydro-
xycoumarin (3) as major product; (ii) subsequently com-
pound 3 was allowed to react with excess 1,2-dichloroethane
in the presence of potassium carbonate to undergo o-chloro-
ethylation to give the monochloroethylated product, 8-allyl-
7-(2-chloroethoxy)coumarin (6); (iii) by the treatment of
compound 6 with potassium tert-butoxide to undergo the
isomerization of allyl group to give c-propenyl function and
to eliminate HCl from chloroethyl group to afford o-vinyl
function in one pot, briefly established an intramolecular
dienes, 8-(1-propenyl)-7-vinyloxycoumarin (7) as the pre-
cursor of RCM; (iv) finally by the cyclization of compound 7
with Grubbs’ catalyst to undergo RCM gave compound 8,
angelicin, in good overall yields.
occurring furanocoumarin is present in the seeds,1 and the
leaves2 of Psoralea grandulosa, and in addition displays a
wide variety of potent and interesting biological activities.
These include antifungal activities,3 inducing S-phase delay
in the rad 14 D mutant,4 inhibition of mutagenesis of 2-
amino-3-methylimidazo[4,5-f]quinoloine,5 inhibitory ef-
fects on the biotransformation of aflatoxin B1 to aflatoxin
B1-8,9-epoxide,6 and inhibition of inducible nitric oxide
synthase.7 Major synthetic strategies utilized include the
following: (i) pyrolysis (650 °C, 0.001 Torr) of methyl 3-(7-
allyloxycoumarin-8-yl)propenoate prepared from 7-hydro-
xycoumarin by 3 steps,8 (ii) vinylation of 8-halo-7-hydroxy-
coumarins, followed by oxidization with Tl(NO3)3 in metha-
nol, and finally by the treatment with acid,9 (iii) via the benz-
annulation reaction of furylcarbene complexes of chro-
mium,10,11 (iv) dihydrobenzofuran derivatives as starting ma-
terial to build the a-pyrone ring through related reactions,12
and (v) via Suzuki or Sonogashira cross-coupling reaction of
corresponding triflate.13 However those methods still have
some disadvantages, including the tedious reaction condi-
tions, the low yield, and the intermediate which is commer-
cially unavailable and difficult to prepare. Thus, it is neces-
sary to develop a more efficient method for the title com-
pound. Until present, no attention has been paid to apply the
RCM reaction, which has been widely utilized in many as-
pects in organic synthesis,14 to the synthesis of angelicin. In
RESULTS AND DISCUSSION
7-Allyloxycourmarin (2), prepared from allyllation of
7-hydroxycoumarin (1) as the general procedure15 in yields
of 95%, was subjected to the Claisen rearrangement with var-
ious conditions to give 8-allyl-7-hydroxycoumarin (3) as ma-
jor product, and 6-allyl-7-hydroxycoumarin (4), together
with 8-methyl-8,9-dihydrofuro[2,3-h]chromen-2-one (5) as
minor products. Some reaction conditions of the Claisen rear-
* Corresponding author. Fax: +886-7-3125339; e-mail: enchwa@kmu.edu.tw

1020 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Tsai and Wang
Scheme I
Br
+
HO
O
HO
O
O
O
O
O
HO
O
O
O
K2CO3
1
2
3
4
+
O
O
O
5
tert-BuO-K+
Grubbs cat.
Cl
Cl
K2CO3
O
O
3
O
O
O
O
O
O
O
Cl
8
6
7
PCy3
Ru
Cl
Cl
Ph
Grubbs cat.
H
PCy3
rangement of 7-allyloxycoumarin (2) have been reported,
such as heating to reflux in N,N-diethylaniline in a closed
vessel, and in refluxing ethylene glycol. However only 8-
allyl-7-hydroxycoumarin (3) was obtained and reported in
84% yields or in 94% crude yields in the condition of
refluxing in N,N-diethylaniline16 or in a closed vessel,17 re-
spectively. On the other hand, not only 8-allyl-7-hydroxy-
coumarin (3) in 70% yields but also 6-allyl-7-hydroxy-
coumarin (4) in 20% yields was obtained if in refluxing ethyl-
ene glycol.18 The minor product, 8-methyl-8,9-dihydrofuro-
[2,3-h]chromen-2-one (5) was paid no attention in running
the Claisen rearrangement of 7-allyloxycoumarin (2) in the
previous studies. The reaction conditions of our studies and
results of the Claisen rearrangement of compound 2 are com-
piled in Table 1.
excess 1,2-dichloroethane under mild reflux in the presence
of anhydrous K2CO3 for 8 h, to undergo monochloroeth-
ylation to give 8-allyl-7-(2-chloroethoxy)coumarin (6) as the
sole product, in yields of 92%. In the case of running the
monochloroethylation of compound 3 with two phases reac-
tion as in our previous report,20 no desired compound 6 was
found due to the opening of the coumarin ring. The structure
of compound 6 can be verified as the following spectral data.
For example, 1H-NMR (CDCl3, 200 MHz) the selected sig-
nals showed three double doublet signals at 3.64 ppm (J =
6.6, 1.4 Hz, 2H), 5.0 ppm (dd, Jcis-gem = 10.0, 1.8 Hz, 1H), and
5.11 ppm (dd, Jtrans-gem = 17.0, 1.8 Hz, 1H), together with one
multiplet signal at 5.98 ppm (1H), indicating the presence of
an allyl group in the molecule. Furthermore two triplet sig-
nals, each one has two protons, respectively at 3.87 ppm (t, J
= 5.8 Hz, 2H), and 4.33 pm (t, J = 5.8 Hz, 2H) indicating the
presence of the OCH2CH2Cl function. Furthermore, the spec-
tral data of 13C-NMR (CDCl3, 50 MHz) revealed fourteen
carbons, matching the carbon required for compound 6. Sub-
sequently, the treatment of compound 6 with one and half
equivalents of potassium tert-butoxide at ambient tempera-
ture isomerized the double bond of allyl group and concomi-
tantly eliminated HCl from the chloroethyl group to generate
8-(1-propenyl)-7-vinyloxycoumarin (7) as the precursor of
These isomers have identical molecular weights, but
have different 1H-NMR spectra, which can be easily identi-
fied. For example, both compound 3, and compound 4 are co-
incident with the spectral data reported in the previous stud-
ies.16,17 However, compound 5, which was paid no attention
in the related Claisen rearrangement,16,17 exhibited the same
spectral data in both proton-NMR and carbon-13 NMR re-
ported by different approaches.19 Subsequently 8-allyl-7-hy-
droxycoumarin (3) dissolved in dry acetone was reacted with

Synthesis of Angelicin
J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004 1021
Table 1. The Claisen rearrangement of 7-allyloxycoumarin (2) under various conditions gave
compounds 3, 4, and 5 in yields of various ratios
Methods*
Compound 3
Compound 4
Compound 5
(% yield)**
(% yield)**
(% yield)**
A. Neat
B. N,N-diethylaniline***
C. Decalin
D. Diphenyl ether
E. N,N-Diethylaniline + silical gel****
57.1%
77.0%
51.5%
53.3%
68.4%
4.1%
11.8%
12.1%
10.7%
8.2%
8.9%
9.1%
34.0%
21.4%
4.3%
* Method A, under argon it was heated at 160 °C without any solvent for 3 h, if heated at
higher temperature, a dark black mass was obtained; Method B, under reflux in N,N-
diethylaniline for 3 h; Method C, under reflux in decalin for 3 h; Method D, under reflux in
diphenyl ether for 3 h; Method E, under reflux in N,N-diethylaniline and silica gel for 3 h.
** Percentage yields were determined by the isolated yields. *** The yields obtained are
lower than that of the same reaction condition previously reported by Clarke, D. J. et al.16
**** When an amount of silica gel (1.5 ´ of compound 2 in weight) was added in carrying
out the Claisen rearrangement, no improvement of the percentage yields of the desired
compound 3 was observed.
RCM in 60% yield in one pot. The evidence of structure 7 was
trometers using CDCl3 as solvent, and with TMS as the inter-
1
based on the spectral data. For example, H-NMR (CDCl3,
nal standard. MS were recorded on Chem/hp/middle instru-
ment, and HRMS were recorded on JEOL, JMSD-200 or on
JEOL, JMS-SX. Elemental analyses were recorded on a
Heraeus CHN-O Rapid Analyzer. Silica gel (230-400 mesh)
for column chromatography and precoated silica gel plates
(60F-254) for TLC were purchased from E. Merck. UV light
(254 nm) was used to detect spots on TLC plates after devel-
opment. Grubbs’ catalyst was purchased from Fluca Com-
pany, and 7-hydroxycourmarin was purchased from Acros
Company.
7-Allyloxycoumarin (2),15,16 8-allyl-7-hydroxycoumarin
(3),16 6-allyl-7-hydroxycoumarin (4),18 and 8-methyl-8,9-
dihydrofuro[2,3-h]chrome-2-one (5)19 were known com-
pounds, and prepared as in general procedures, respectively.
200 MHz): the selected signals showed one methyl signal
with double doublet at 1.98 ppm (J = 6.6, 1.8 Hz) indicating
the migration of allylic double bond from terminal end to in-
ternal one, and three one-proton olefinic signals with double
doublet, respectively at 4.58 ppm (dd, Jcis-gem = 6.0, 2.0 Hz),
4.86 ppm (dd, Jtrans-gem = 13.6, 2.0 Hz), 6.61 ppm (dd, Jtrans-cis
=
13.6, 6.0 Hz) exhibiting the presence of one vinyl group in the
molecule of compound 7. Furthermore, fourteen carbons in
the 13C-NMR spectrum and m/z 228 (M+) in the EI-MS (70
eV) spectrum, that all coincident with the molecular formula,
C14H12O3 required for compound 7, were found. Finally, the
ring-closing metathesis with Grubbs’ catalyst gave angelicin
(8) in yields of 90%. All data obtained from compound 8 are
matched with that of the natural product, angelicin.11
In conclusion, based on the Claisen rearrangement of
7-allyloxycoumarin, via a sequence of reactions to easily
build up the precursor of RCM, and followed by olefin ring-
closing metathesis, successfully gave angelicin in 36% over-
all yields. The application of our synthetic strategy to the
preparation of some potential compounds is currently in
progress in our laboratory.
Preparation of 8-Allyl-7-(2-chloroethoxy)coumarin (6)
To 8-allyl-7-hydroxycoumarin, compound 4 (10.1 g,
0.05 mol), dissolved in dry acetone (100 mL) was added with
anhydrous K2CO3 (17.25 g, 0.125 mol) and under reflux for
20 min., then was injected with excess 1,2-dichloroethane
(59 mL, 0.75 mol). The mixture was under reflux for 48 h,
and then was filtered through Celite 545. The filtrate was
concentrated under vacuum. The residue was dissolved in
ethyl acetate (100 mL), and washed with brine (20 mL ´ 3).
The organic solution was dried with anhydrous MgSO4, and
then was filtered. The filtrate was concentrated, and the resi-
due was subjected to silica gel chromatographic column
(EtOAc/n-hexane = 1/2) to give pure 8-allyl-7-(2-chloroeth-
oxy)coumarin (6).
EXPERIMENTAL
Melting points (Yanaco micro melting-point apparatus)
1
are uncorrected. H-NMR and 13C-NMR spectra were re-
corded on Varian Gemini-200 or Varian Unity Plus 400 spec-

1022 J. Chin. Chem. Soc., Vol. 51, No. 5A, 2004
Tsai and Wang
Pure 8-allyl-7-(2-chloroethoxy)coumarin (6) (12.2 g,
92%) was obtained as colorless needle crystals, mp 142 °C,
Rf 0.4 (EtOAc/n-hexane = 1/2), 1H-NMR (CDCl3, 200 MHz)
d 3.64 (dd, J = 6.6, 1.4 Hz, 2H, CH2CH=CH2), 3.87 (t, J = 5.8
Hz, 2H, OCH2CH2Cl), 4.33 (t, J = 5.8 Hz, 2H, OCH2CH2Cl),
5.0 (dd, Jcis-gem = 10.0, 1.8 Hz, 2H, CH2CH=CH2), 5.11 (dd,
Jtrans-gem = 17.0, 1.8 Hz, 1H, CH2CH=CH2), 5.98 (m, 1H,
CH2CH=CH2), 6.27 (d, J = 9.5 Hz, H-3), 6.82 (d, J = 8.6 Hz,
1H, H-6), 7.33 (d, J = 8.6 Hz, 1H, H-5), 7.64 (d, J = 9.5 Hz,
H-4); 13C-NMR (CDCl3, 50 MHz) d 26.94, 41.69, 68.73,
108.29, 113.46, 113.52, 115.65, 116.86, 126.63, 134.95,
143.54, 153.00, 158.82, 161.05; EI-MS 266 (M+2, 20), 264
(M+, 64), 229 (67), 201 (37), 187 (100), 173 (62), 159 (57),
128 (32), 115 (45); Anal calcd for C14H13ClO3: C, 63.52; H,
4.95. Found: C, 63.46; H, 5.06.
mixture was stirred for 72 h at ambient temperature under dry
argon. Finally the solvent was removed in vacuo, and the re-
sulting residue was subjected to a silica gel chromatographic
column (EtOAc/n-hexane = 1/2) or to be distilled under vac-
uum to give pure angelicin (8).
Angelicin (8) (2.17 g, 90%) was obtained as colorless
needle crystals: bp = 98-104 °C (4 mmHg), mp 139 °C [lit.,13
137-137.5], Rf 0.44 (EtOAc/n-hexane = 1/2), 1H-NMR
(CDCl3, 200 MHz) d 6.40 (d, J = 9.6 Hz, 1H, H-3), 7.14 (dd, J
= 2.2, 0.6 Hz, 1H, H-9), 7.38 (d, J = 8.5 Hz, 1H, H-5), 7.45
(dd, J = 8.5, 0.6 Hz, 1H, H-6), 7.70 (d, J = 2.2 Hz, H-8), 7.82
(d, J = 9.6 Hz, 1H, H-4), 13C-NMR (CDCl3, 50 MHz) d
104.07, 108.77, 113.51, 114.11, 116.92, 123.80, 114.45,
145.86, 148.51, 157.34, 160.77, EI-MS (70 eV) m/z 186 (M+,
83), 159 (12), 158 (100), 130 (24), 102 (41). Anal calcd for
C11H6O3: C, 70.97; H, 3.25. Found: C, 70.99; H, 3.42.
Preparation of 8-(1-propenyl)-7-(vinyloxy)coumarin (7)
Under dry nitrogen 8-Allyl-7-(2-chloroethoxy)coumarin
(10 g, 38 mmol), dissolved in anhydrous THF (80 mL), was
added potassium tert-butoxide (6.4 g, 57 mmol) and stirred at
ambient temperature for 5 h. After the end of reaction, the
suspension was filtered, and washed through filter paper with
ethyl acetate (25 mL ´ 3). The organic filtrate was dried with
MgSO4. After filtration, the solution was concentrated under
vacuum; the resulting residue was subjected to silica gel
chromatographic column (EtOAc/n-hexane = 1:2) to give
pure 8-(1-Propenyl)-7-(vinyloxy)coumarin (7).
ACKNOWLEDGEMENTS
We are grateful to NSC, Taiwan, for financial support,
to Mr. Wen-Hsiung Lu for measuring elemental analysis, and
to Miss Chyi-Jia Wang for recording proton and carbon NMR
spectra.
Received January 13, 2004.
Pure 8-(1-propenyl)-7-(vinyloxy)coumarin (7) (5.2 g,
60%) was obtained as colorless crystals, mp 102 °C, Rf 0.4
(EtOAc/n-hexane = 1/2), 1H-NMR (CDCl3, 400 MHz) d 1.98
(dd, J = 6.6, 1.8 Hz, 3H, CH=CHCH3), 4.58 (dd, Jcis-gem = 6.0,
2.0 Hz, 1H, OCH=CH2), 4.86 (dd, Jtrans-gem = 13.6, 2.0 Hz, 1H,
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